oru.sePublikationer
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Diastereomers of the Brominated Flame Retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane Induce Androgen Receptor Activation in the HepG2 Hepatocellular Carcinoma Cell Line and the LNCaP Prostate Cancer Cell Line
Örebro University, School of Science and Technology.
Örebro University, School of Science and Technology.
Örebro University, School of Science and Technology.ORCID iD: 0000-0002-4954-926X
Wellington Laboratories Inc., Research Division, Guelph, Ontario, Canada.
Show others and affiliations
2009 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 117, no 12, 1853-1859 p.Article in journal (Refereed) Published
Abstract [en]

Background: Reported incidences of prostate cancer and masculinization of animals indicate a release of compounds with androgenic properties into the environment. Large numbers of environmental pollutants have been screened to identify such compounds; however, not until recently was 1,2-dibromo-4-(1,2-dibromoethyl)cyclohex​ane (TBECH) identified as the first potent activator of the human androgen receptor (hAR). TBECH has been found in beluga whales and bird eggs and has also been found to be maternally transferred in zebrafish.

Objectives: In the present study we investigated interaction energies between TBECH diastereomers (α, β, γ, and δ) and the hAR, and their ability to activate the receptor and induce prostate-specific antigen (PSA) expression in vitro.

Methods: We performed computational modeling to determine interaction energies between the ligand and the AR ligand-binding site, and measured in vitro competitive binding assays for AR by polarization fluorometry analysis. We used enzyme-linked immunosorbent assays to determine PSA activity in LNCaP and HepG2 cells.

Results: We found the γ and δ diastereomers to be more potent activators of hAR than the α and β diastereomers, which was confirmed in receptor binding studies. All TBECH diastereomers induced PSA expression in LNCaP cells even though the AR present in these cells is mutated (T877A). Modeling studies of LNCaP AR revealed that TBECH diastereomers bound to the receptor with a closer distance to the key amino acids in the ligand-binding domain, indicating stronger binding to the mutated receptor.

Conclusions: The present study demonstrates the ability of TBECH to activate the hAR, indicating that it is a potential endocrine disruptor.

Place, publisher, year, edition, pages
National Institute of Environmental Health Science , 2009. Vol. 117, no 12, 1853-1859 p.
Keyword [en]
androgen, brominated flame retardant, endocrine disruptor
National Category
Natural Sciences Chemical Sciences Environmental Sciences Biological Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-9678DOI: 10.1289/ehp.0901065ISI: 000272474600026PubMedID: 20049203Scopus ID: 2-s2.0-75349109314OAI: oai:DiVA.org:oru-9678DiVA: diva2:292802
Available from: 2010-02-09 Created: 2010-02-09 Last updated: 2017-02-17Bibliographically approved
In thesis
1. Androgen receptors and endocrine disrupting substances
Open this publication in new window or tab >>Androgen receptors and endocrine disrupting substances
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Throughout the animal kingdom, organisms are dependent on substances such as steroid hormones to help them maintain internal balances. Examples of important tasks that are under regulation of steroid hormones are somatic and gonadal development, sexual performance and behavior (both social and sexual) as well as sex differentiation. Balance in the biology of reproduction is important for all organisms, and is sensitive to alterations and disturbances. If the environment is altered in a manner that lead to higher estrogenic or androgenic levels, the sex ratio of organisms that do not rely on genetic differences in the sex differentiation, will be biased towards more females or males in the population. It has been known for some time that there are pollutants in the environment that affect steroid pathways, such as the estrogenic and thyroid systems, but not much has been known about the androgenic systems. Examples of populations being masculinized have been recorded, and estrogenic compounds have been known to act as antiandrogens, but not until recently the first androgen agonist was identified. We used a combination of in vitro and computational modeling to identify the brominated flame retardant, 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane, as a potent androgen agonist to the human androgen receptor.

In addition to this we cloned and characterized the androgen receptor from, a frequently used model organism, zebrafish (Danio rerio) as a receptor primarily activated by 11-ketotestosterone. This is a feature the zebrafish share with several other teleost fishes, such as the three-spined stickleback. Thus fish androgen receptors differ from most mammalian androgen receptors, where dihydrotestosterone is the most potent activator.

 

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. 64 p.
Series
Örebro Studies in Life Science, 5
Keyword
Androgen receptor, Brominated flame retardant, TBECH, Endocrine disruptor
National Category
Biological Sciences Natural Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-9679 (URN)978-91-7668-714-7 (ISBN)
Public defence
2010-02-26, Hörsal P2, Örebro, 10:15 (English)
Opponent
Supervisors
Available from: 2010-02-10 Created: 2010-02-09 Last updated: 2011-05-11Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedScopus

Search in DiVA

By author/editor
Khalaf, HazemLarsson, AndersBerg, HåkanOlsson, Per-Erik
By organisation
School of Science and Technology
In the same journal
Journal of Environmental Health Perspectives
Natural SciencesChemical SciencesEnvironmental SciencesBiological Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 267 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf